Epilepsy is defined by recurrent episodes of seizures, which are brief involuntary behavioral alterations caused by paroxysmal intense electrical discharges in the brain.
Epilepsy affects up to 1% of the population (over 50 million people) (1) and is resistant to drug therapy in at least 20% of cases (2). It represents a serious burden to society and to affected individuals. Even with the best current treatments, over 25% of patients continue to have seizures which are seriously disruptive to their lives.
Epilepsy can be focal (arising from a specific brain area) or generalised (arising from both hemispheres). People with focal-onset epilepsy are especially prone to pharmacoresistance (3). The epileptogenic zone in such cases is often restricted to a small region that can often be localized with imaging and electrophysiological techniques (4). However, surgical removal of the seizure focus can successfully treat only about 5% of pharmacoresistant patients, and is often inappropriate in focal neocortical epilepsy because of proximity to eloquent cortex (5, 6).
WO00/18903 describes a system for therapy of epilepsy and intractable pain, as well as for cardiac arrhythmias. in which so-called “electrical silencing” genes are transferred into cells with sensitive control of the transgene expression. Examples given are an ecdysone-inducible promoter which drives the expression inwardly rectifying potassium channels in polycistronic adenoviral vectors. It is reported that while normal electrical activity is not affected, after the induction of gene expression excitability is suppressed.
Furthermore gene therapy targeted to the epileptogenic zone has been shown to be effective in rodent models of epilepsy including focal neocortical epilepsy (7).
However, viral delivery of transgenes that alter excitability permanently may impair essential function of circuits near the seizure focus. An attractive strategy would be to suppress circuit excitability ‘on demand’ upon detection of a seizure. Recently progress in optogenetic seizure suppression in rodents has shown that this is, in principle, feasible (7-9). One of the main limitations to clinical translation is the need to deliver light of the appropriate wavelength, intensity and duration to the region of transduced neurons. This necessitates the implantation of optical devices and suffers from the strong attenuation of light in brain tissue.
It can thus be seen that novel methods of treating epilepsy, such as focal epilepsy, would provide a contribution to the art.